Identification of signatures for neurodegeneration diseases diagnoses

Abstract

The present invention is directed to diagnostic methods for differentiating Alzheimer's Disease (AD) patients and Frontotemporal Dementia (FTD) patients versus Healthy Controls. The invention also provides methods for distinguishing between these two neurodegenerative diseases AD and FTD, a method for monitoring the progression of AD and/or FTD, a method for determining the efficacy of an AD and/or FTD therapy and a method for screening compounds to be used against AD and/or FTD.

1 . A diagnostic method to distinguish Alzheimer's patient subjects, comprising determining in a plasma sample of said subject the levels of at least one metabolic marker selected from the list consisting of amino Acids and Biogenic amines Aminoadipic acid (alpha-AAA) and/or Butane-1,4-diamine (putrescine) and comparing the levels of said marker or markers with respect to the levels of the same marker or markers in a HC patient or with respect to a reference value, wherein the subject is classified as suffering AD or as having an increased risk of suffering from AD if the expression levels of Aminoadipic acid are decreased with respect to the levels of the same marker or markers in a HC patient or with respect to a reference value and/or if the levels of putrescine are increased with respect to the levels of the same marker or markers in a HC patient or with respect to a reference value. 
     
     
         2 . The diagnostic method of  claim 1 , wherein the metabolic marker is Aminoadipic acid (alpha-AAA). 
     
     
         3 . The diagnostic method of  claim 1 , wherein the metabolic marker is putrescine. 
     
     
         4 . The diagnostic method of  claim 1 , wherein the method comprises determining the levels of each of the metabolites of the list consisting of aminoadipic acid (alpha-AAA), butane-1,4-diamine (putrescine), arginine, ornithine, glutamic acid, Lyso PC a C18:0, PC aa C34:3, PC ae C30:0, and PC ae C36:0 and the presence of allele APOE4, and comparing the levels of said markers with respect to the levels of the same markers in a HC patient or with respect to a reference value, wherein the subject is classified as suffering AD or as having an increased risk of suffering from AD if there is an increased level(s) of Ornithine, Putrescine, PC aa C34:3, and PC ae C30:0 and the presence of allele APOE4 and a decreased level(s) of L-Arginine, L-Glutamic Acid, Alpha-AAA, Lyso PC a C18:0 and PC ae C36:0. 
     
     
         5 . In vitro use of a diagnostic kit or device comprising reagents capable of measuring the levels of at least one metabolic marker selected from the list consisting of amino Acids and Biogenic Aminoadipic acid (alpha-AAA) and/or Butane-1,4-diamine (putrescine) in a plasma sample, for distinguish Alzheimer's patient subjects from subjects not suffering from Alzheimer's disease. 
     
     
         6 . The use according to  claim 5 , wherein said kit or device comprises reagents capable of measuring the levels of Aminoadipic acid (alpha-AAA) in a plasma sample. 
     
     
         7 . The use according to  claim 5 , wherein said kit or device comprises reagents capable of measuring the levels of putrescine in a plasma sample. 
     
     
         8 . The use according to  claim 5 , wherein said kit or device comprises reagents capable of measuring the levels of aminoadipic acid (alpha-AAA), butane-1,4-diamine (putrescine), arginine, ornithine, glutamic acid, Lyso PC a C18:0, PC aa C34:3, PC ae C30:0, PC ae C36:0 and the presence of the allele APOE4 in a plasma sample. 
     
     
         9 . A method for determining the efficacy of a therapy for AD in a subject, comprising determining in a plasma sample of said subject the levels of at least one metabolic marker selected from the list consisting of amino Acids and Biogenic amines: aminoadipic acid (alpha-AAA) and/or butane-1,4-diamine (putrescine) and comparing the levels of said marker or markers with respect to the levels of the same marker or markers in a HC patient or with respect to a reference value, wherein the therapy is efficient if the expression levels of aminoadipic acid are increased with respect to the levels of the same marker or markers in a HC patient or with respect to a reference value and/or if the levels of putrescine are decreased with respect to the levels of the same marker or markers in a HC patient or with respect to a reference value. 
     
     
         10 . The method of  claim 9 , wherein the method comprises determining the levels of each of the metabolites of the list consisting of aminoadipic acid (alpha-AAA), butane-1,4-diamine (putrescine), arginine, ornithine, glutamic acid, Lyso PC a C18:0, PC aa C34:3, PC ae C30:0, PC ae C36:0 and the presence of allele ApoE4, and comparing the levels of said markers with respect to the levels of the same markers in a HC patient or with respect to a reference value, wherein the therapy is efficient if there is a decreased level(s) of ornithine, putrescine, PC aa C34:3, PC ae C30:0 and no detection of the presence of allele APOE4 and an increased level(s) of L-Arginine, L-Glutamic Acid, Alpha-AAA, Lyso PC a C18:0 and PC ae C36:0. 
     
     
         11 . A method for monitoring the progression of AD in a subject, comprising determining in a plasma sample of said subject the levels of at least one metabolic marker selected from the list consisting of amino Acids and Biogenic amines: aminoadipic acid (alpha-AAA) and/or butane-1,4-diamine (putrescine) and comparing the levels of said marker or markers with respect to the levels of the same marker or markers the same subject at an earlier time point or with respect to a reference value, wherein the disease is progressing if the expression levels of aminoadipic acid are decreased with respect to the levels of the same marker or markers in the same subject at an earlier time point or with respect to a reference value and/or if the levels of putrescine are increased with respect to the levels of the same marker or markers in the same subject at an earlier time point or with respect to a reference value. 
     
     
         12 . The method of  claim 11 , wherein the method comprises determining the levels of each of the metabolites of the list consisting of aminoadipic acid (alpha-AAA), butane-1,4-diamine (putrescine), arginine, ornithine, glutamic acid, Lyso PC a C18:0, PC aa C34:3, PC ae C30:0, and PC ae C36:0 and the presence of allele APOE4, and comparing the levels of said markers with respect to the levels of the same markers in the same subject at an earlier time point or with respect to a reference value, wherein the disease is progressing if there is an increased level(s) of ornithine, putrescine, PC aa C34:3, PC ae C30:0 and the presence of allele APOE4 and a decreased level(s) of L-Arginine, L-Glutamic Acid, Alpha-AAA, Lyso PC a C18:0 and PC ae C36:0 with respect to the levels of the same marker or markers in the same subject at an earlier time point or with respect to a reference value. 
     
     
         13 . In vitro use of a kit or device comprises reagents capable of measuring the levels of aminoadipic acid (alpha-AAA), butane-1,4-diamine (putrescine), arginine, ornithine, glutamic acid, Lyso PC a C18:0, PC aa C34:3, PC ae C30:0, PC ae C36:0 and the presence of allele APOE4 in a plasma sample, for the method for determining the efficacy of a therapy for AD in a subject as defined in  claim 10 . 
     
     
         14 . In vitro use of a kit or device comprises reagents capable of measuring the levels of aminoadipic acid (alpha-AAA), butane-1,4-diamine (putrescine), arginine, ornithine, glutamic acid, Lyso PC a C18:0, PC aa C34:3, PC ae C30:0, PC ae C36:0 and the presence of allele APOE4 in a plasma simple, for the method for monitoring the progression of AD in a subject as defined in  claim 12 . 
     
     
         15 . A kit or device comprises reagents capable of measuring the levels of aminoadipic acid (alpha-AAA), butane-1,4-diamine (putrescine), arginine, ornithine, glutamic acid, Lyso PC a C18:0, PC aa C34:3, PC ae C30:0, PC ae C36:0 and the presence of allele APOE4 in a plasma sample.